TY - JOUR
T1 - Promoter hypermethylation of SFRP1 is an allele fraction-dependent prognostic biomarker in metastatic pancreatic ductal adenocarcinoma
AU - Stubbe, Benjamin
AU - Stoico, Malene P
AU - Terp, Simone K
AU - Madsen, Poul H
AU - Lundbye-Christensen, Søren
AU - Hansen, Carsten P
AU - Poulsen, Laurids Ø
AU - Rasmussen, Louise S
AU - Yilmaz, Mette N
AU - Jensen, Lars H
AU - Hansen, Torben F
AU - Pfeiffer, Per
AU - Larsen, Anders C
AU - Krarup, Henrik B
AU - Pedersen, Inge S
AU - Hasselby, Jane P
AU - Johansen, Astrid Z
AU - Chen, Inna M
AU - Johansen, Julia S
AU - Thorlacius-Ussing, Ole
AU - Henriksen, Stine D
N1 - Copyright © 2025 Stubbe, Stoico, Terp, Madsen, Lundbye-Christensen, Hansen, Poulsen, Rasmussen, Yilmaz, Jensen, Hansen, Pfeiffer, Larsen, Krarup, Pedersen, Hasselby, Johansen, Chen, Johansen, Thorlacius-Ussing and Henriksen.
PY - 2025
Y1 - 2025
N2 - INTRODUCTION: Metastatic pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Promoter hypermethylation of SFRP1 (phSFRP1) in cell-free DNA is an established prognostic biomarker in PDAC. We used digital droplet PCR (ddPCR) to examine whether the prognostic impact of phSFRP1 was allele fraction (AF) dependent.METHODS: Prospectively collected plasma samples were analyzed blinded. Dual-strand methylation ddPCR assays were designed for SFRP1, with single-strand assay for the reference gene EPHA3. Patients were stratified into unmethylated SFRP1 (umSFRP1), low phSFRP1 AF (phSFRP1low), and high phSFRP1 AF (phSFRP1high). Survival was assessed with Kaplan-Meier curves. The 3-, 6-, and 12-month absolute risk difference (ARD) was calculated, and performance assessed with ROC analyses.RESULTS: Overall, 354 patients were included. Patients with umSFRP1 (n=137) had a mOS of 9.1 months compared to 7.2 months in phSFRP1low (n=78) and 3.4 months in phSFRP1high (n=143, P<0.01). phSFRP1high was associated with increased mortality at 3 (ARD 26%, 95%CI: 15, 37), 6 (ARD 37%, 95%CI: 26, 48), and 12 months (ARD 23%, 95%CI: 14, 33). phSFRP1low was associated with increased mortality at 12 months (ARD 13%, 95%CI: 2, 25) but not at 3 (ARD -3%, 95%CI: -13, 8) or 6 months (ARD 3%, 95%CI: -10, 17). phSFRP1 significantly improved performance in predicting mortality compared to only clinical variables (AUC: 0.70-0.71 vs. 0.54-0.57).DISCUSSION: Patients with phSFRP1high had significantly shorter survival than phSFRP1low or umSFRP1, indicating AF-dependent prognostic effects. phSFRP1low had a worse prognosis than umSFRP1 at only 12 months, indicating dynamic changes. This could help personalize the treatment of PDAC.
AB - INTRODUCTION: Metastatic pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Promoter hypermethylation of SFRP1 (phSFRP1) in cell-free DNA is an established prognostic biomarker in PDAC. We used digital droplet PCR (ddPCR) to examine whether the prognostic impact of phSFRP1 was allele fraction (AF) dependent.METHODS: Prospectively collected plasma samples were analyzed blinded. Dual-strand methylation ddPCR assays were designed for SFRP1, with single-strand assay for the reference gene EPHA3. Patients were stratified into unmethylated SFRP1 (umSFRP1), low phSFRP1 AF (phSFRP1low), and high phSFRP1 AF (phSFRP1high). Survival was assessed with Kaplan-Meier curves. The 3-, 6-, and 12-month absolute risk difference (ARD) was calculated, and performance assessed with ROC analyses.RESULTS: Overall, 354 patients were included. Patients with umSFRP1 (n=137) had a mOS of 9.1 months compared to 7.2 months in phSFRP1low (n=78) and 3.4 months in phSFRP1high (n=143, P<0.01). phSFRP1high was associated with increased mortality at 3 (ARD 26%, 95%CI: 15, 37), 6 (ARD 37%, 95%CI: 26, 48), and 12 months (ARD 23%, 95%CI: 14, 33). phSFRP1low was associated with increased mortality at 12 months (ARD 13%, 95%CI: 2, 25) but not at 3 (ARD -3%, 95%CI: -13, 8) or 6 months (ARD 3%, 95%CI: -10, 17). phSFRP1 significantly improved performance in predicting mortality compared to only clinical variables (AUC: 0.70-0.71 vs. 0.54-0.57).DISCUSSION: Patients with phSFRP1high had significantly shorter survival than phSFRP1low or umSFRP1, indicating AF-dependent prognostic effects. phSFRP1low had a worse prognosis than umSFRP1 at only 12 months, indicating dynamic changes. This could help personalize the treatment of PDAC.
UR - http://www.scopus.com/inward/record.url?scp=105007624268&partnerID=8YFLogxK
U2 - 10.3389/fonc.2025.1568386
DO - 10.3389/fonc.2025.1568386
M3 - Journal article
C2 - 40492125
SN - 2234-943X
VL - 15
SP - 1568386
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1568386
ER -